Abstract 209: A Natural p300-specific Histone Acetyltransferase Inhibitor, Curcumin, Represses Hypertrophic Responses in Cardiac Myocytes and Prevents the Development of Hypertension-induced Heart Failure in Salt-sensitive Dahl Rats
Introduction: Hypertrophic stimuli activate cardiac transcription factors such as SRF, MEF-2 and a zinc finger protein GATA-4 and modulate gene expression in cardiac myocytes. These changes finally lead to the development of heart failure in vivo. Acetylation is one of critical mechanisms that activate these transcriptional factors, and mediated, in part, by an intrinsic histone acetyltransferase (HAT) such as a transcriptional coactivator p300. However, a pharmacological heart failure therapy that targets this pathway has not been established. One of compounds that have been reported to inhibit p300-HAT activity is a natural compound, curcumin, a major curcumanoid in the spice turmeric isolated from Curcuma longa. This compound inhibits histone acetylation in vitro and represses p300-mediated chromatin transcription in cultured HeLa cells.
Methods and results: First, we examined effects of curcumin on primary cardiac myocytes from neonatal rats in culture. Curcumin (5–10∈¼M) repressed phenylephrine-induced hypertrophic responses such as myofibrillar organization, increase in cell size and transactivation of the atrial natriuretic factor and beta-myosin heavy chain promoters. Curcumin also blocked phenylephrine-induced increase in acetylation and DNA binding activity of GATA-4 as well as acetylation of histones. Second, to determine whether curcumin can prevent the development of heart failure in vivo, we have utilized a salt-sensitive Dahl (DS) rat model of hypertension. In this model, left ventricular concentric hypertrophy at the age of 11 weeks is followed by decompensated heart failure at the age of 17 weeks. We randomized 11-week-old DS rats (n=56) to oral chronic treatment with curcumin (50 mg/Kg/day) or vehicle. At the age of 17 weeks, curcumin significantly ameliorated the survival rate (curcumin: 76%, vehicle: 44%, p<0.001). However, blood pressure did not differ between curcumin- and vehicle-treated groups.
Conclusion: A natural compound, curcumin represses hypertrophic responses in cardiac myocytes, in part, by perturbing a p300-dependent transcriptional pathway, and prevents the development of hypertension-induced decompensated heart failure in vivo.